Compounds which are inhibitors of human immunodeficiency virus (HIV) protease are useful for inhibiting HIV protease in vitro and in vivo and are useful for inhibiting an HIV infection. Certain HIV protease inhibitors comprise a moiety which is a substituted 2,5-diamino-3-hydroxyhexane. HIV protease inhibitors of particular interest are compounds having formula 1: ##STR2## wherein A is R.sup.2 NHCH(R.sup.1)C(O)-- and B is R.sup.2a or wherein A is R.sup.2a and B is R.sup.2 NHCH(R.sup.1)C(O)-- wherein R.sup.1 is lower alkyl and R.sup.2 and R.sup.2a are independently selected from --C(o)--R.sup.3 --R.sup.4 wherein at each occurrence R.sup.3 is independently selected from O, S and --N(R.sup.5)-- wherein R.sup.5 is hydrogen or lower alkyl and at each occurrence R.sup.4 is independently selected from heterocyclic or (heterocyclic)alkyl; or a pharmaceutically acceptable salt, prodrug or ester thereof. Compounds of formula 1 are disclosed in U.S. Pat. No. 5,354,866, issued Oct. 11, 1994, and U.S. Pat. No. 5,541,206, issued Jul. 30, 1996.
A preferred HIV protease inhibitor having formula I is a compound of formula II: ##STR3## or a pharmaceutically acceptable salt, prodrug or ester thereof. The compound having formula II is disclosed in U.S. Pat. No. 5,421,206, issued Jul. 30, 1996 (the '206 patent).
An intermediate which is especially useful for preparing compounds having formula II is a compound having the formula 3 or an acid addition salt thereof: ##STR4##
The preparation of compounds having formula 3 has been disclosed in the '206 patent and International Patent Application No. WO 96/16050 published May 30, 1996 (the '050 application).
Methods for the preparation of 5-hydroxymethylthiazole disclosed in U.S. Pat. No. 5,541,206 include those shown in Scheme 1. However, neither of these methods is suited for large scale production of pure 5-hydroxymethylthiazole. ##STR5##
The '050 application discloses a preparation in which 2-chloro-5-chloro-methylthiazole is reacted with a carboxylic acid salt in the presence of a phase transfer catalyst. This provides an ester which is then hydrolyzed to provide 2-chloro-5-hydroxymethylthiazole. Dechlorination of the chloroalcohol is then accomplished by catalytic hydrogenation. Drawbacks which occur when using this method are the additional hydrolysis step required to obtain the alcohol and difficulties in removing the quaternary ammonium phase transfer catalyst.
Thus, there is a continuing need for improved processes for the preparation of 5-hydroxymethylthiazoles.